asthma, severe asthma, J Allergy Clin Immunol, IL, Crit Care Med, airway function, asthma symptoms, persistent asthma, N Engl J Med, interleukin, smooth muscle, asthma control, Allergy, Clin Exp Allergy, monoclonal antibody, Eur Respir J, clinical trial, asthma patients, Clin Immunol, Brugues J. Costs, Lotvall J. Regulation, Pulmon Med, clinical trials, Arch Intern Med, adolescent patients, Lotvall J. Allergen-induced, Eur J Immunol, eosinophilic asthma, J Pediatr, atopic asthma, Epithelial cells, Basement membrane, Mast cells, Pediatr Allergy Immunol, childhood asthma, National Jewish Health, symptoms of asthma, treatments for asthma, children with asthma, allergic asthma, clinical development
STATE OF THE ART REVIEW
Asthma: pathogenesis and novel drugs for treatment
J Tod Olin, Michael E Wechsler
Pediatric Exercise Tolerance Center, Department of Pediatrics, National Jewish Health, Denver, CO , USA Asthma Program, Department of Medicine, National Jewish Health, Denver, CO, USA Correspondence to: M E Wechsler [email protected]
Cite this as: BMJ ; :g doi: . /bmj.g
ABSTRACT Asthma affects almost million people in the United States and more than million people worldwide. Of these, - % have severe asthma, which is refractory to commonly available drugs. New drugs are needed because those that are currently available cannot control symptoms and exacerbations in all patients and can cause adverse reactions. In the past years, there have been substantial advances in the understanding of asthma genetics, airway biology, and immune cell signaling. These advances have led to the development of small molecule therapeutics and biologic agents that may improve asthma care in the future. Several new classes of asthma drugs--including ultra long acting agonists and modulators of the interleukin (IL- ), IL- , IL- , and IL- pathways--have been evaluated in randomized controlled trials
. Other new drug classes--including dissociated corticosteroids, CXC chemokine receptor antagonists
, toll-like receptor agonists, and tyrosine kinase inhibitors--remain in earlier phases of development. Despite some preliminary efficacy data, there is insufficient evidence to make strong recommendations about the use of these newer agents. future research
on the clinical efficacy of these biologic agents, the effect of newer agents on severe asthma in pediatric patients, and the biology of non-eosinophilic and corticosteroid resistant asthma is needed to reduce the morbidity of asthma worldwide.
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Introduction Asthma is a heterogeneous disease characterized by varying levels of bronchoconstriction, airway hyper-responsiveness, mucus secretion, and chronic inflammation. Asthma a ects about million people worldwide, causes deaths annually, and is responsible for billions of dollars of healthcare expenditure. Although death from asthma has decreased with the regular use of inhaled glucocorticoids, the global impact of asthma remains high, and the prevalence of asthma seems to be increasing. - There is a clear need for new drugs for asthma that overcome the shortcomings of those that are currently available. This review focuses on the need for new treatments for asthma, important pathophysiologic pathways, and drugs that are currently available or in late phase clinical development. Each drug is discussed in terms of its e ect on symptoms, physiology, or exacerbations, depending on the relevant clinical trials. Because most of the data on newer agents are for use in adults only, the review focuses mainly on adults. However, pediatric data are mentioned when available. Epidemiology Asthma symptoms are reported in . % of - year old children worldwide. In , in the United States alone,
an estimated . million adults and seven million children were reported to have asthma. Although the reported prevalence of the diagnosis and the symptoms of asthma vary globally, possibly because of variable diagnostic criteria and available con rmation strategies in epidemiologic studies, speci c groups in the population have higher rates of asthma than the general population. For example, the prevalence of asthma seems to be higher in urban areas
than in rural ones. In the US, race and ethnicity strongly a ect the prevalence of asthma, with the highest rates occurring in Puerto Rican, multiple race, and AfricanAmerican people, respectively. Asthma is more common in children and people on a low income than in the general population -- % of African-American children and . % of children from low income families have asthma. SOURCES AND SELECTION CRITERIA The references from this review came from a PubMed search from to May and our personal libraries. To obtain a broad range of articles, we used the term "asthma" with the filters "clinical trials" and "year". We initially screened more than articles and gave particular attention to articles on drugs that were in the late phase of development. The reference lists of clinical trials were also screened and relevant articles included. The systematic review
from the Global Initiative for Asthma was also included.
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Independent of high prevalence, increases in preva-
lence of asthma are outstripping the e ect of improved
diagnostic capabilities in certain parts of the world.
In the US from
the overall prevalence of
asthma increased from . % to . %.
Reasons behind the increased prevalence are unclear,
but several plausible hypotheses have been put forward.
Increasing rates of atopy in Western society probably
contribute to the increased prevalence. In addition,
exposure to particulate matter
is associated with higher
rates of asthma and it clearly affects asthma symp-
toms. As the prevalence of smoking and obesity has
increased, it has become apparent that the frequency
of asthma is higher in children of smokers and that the
severity of obesity is strongly associated with asthma in
adult women. Changes in the diversity and timing of
microbial exposures during development may also play
a role. Finally, there is evidence that maternal and
childhood dietary factors modulate the likelihood of the
development of asthma. Increased understanding
of the proposed mechanisms behind these increases in
prevalence may ultimately lead to improved preventive
and therapeutic strategies.
In other parts of the world the trend of increased preva-
lence is not so clear. The ISAAC III study showed that the
prevalence of asthma symptoms is declining in western
Europe and some English speaking countries, while
simultaneously increasing in many Developing Nations
Impact of asthma
Asthma has a substantial impact on public health.
Asthma causes an estimated
deaths per year
worldwide. In the US in
, % of patients with
asthma were admitted to hospital (>
and . % were treated in an emergency department
(more than two million visits). Around % of patients
with asthma report an asthma attack in the previous
year, and % of patients report exacerbations that lead
to more than one day of missed school or work over that
Patients with asthma are less likely to be employed
than those without asthma, and they are more likely to
have activity limitation at their place of employment, at
school, or within the home. Similarly, children with
asthma have higher rates of school absenteeism than
controls, despite available treatments. The average
US patient with asthma incurred
in additional healthcare expenses than controls
from to , accounting for bn- bn in costs
attributable to asthma.
Specific populations of patients with asthma have
higher rates of mortality and morbidity. In the US, death
from asthma is % higher in female than in male
patients, % higher in African-Americans than in white
people, and roughly seven times higher in people over
years than in children. Children have higher rates of
visits to the doctor's surgery and emergency department
than adults. Importantly, patients with severe or di -
cult to treat asthma ( - % of patients with asthma) have
higher levels of morbidity than the general population
Asthma phenotypes, endotypes, and representative inflammatory signatures To decrease the impact of asthma through treatment directed towards speci c groups of patients, research in the past two decades has attempted to de ne asthma subtypes. In recent years, multiple in ammatory pro les and multiple phenotypic clusters of patients with asthma have been identi ed, although precise de nitions of these clusters remain elusive. Although patients can be subdivided according to several clinical, physiologic, radiographic, and pathologic variables, multiple analyses suggest that adult patients are likely to fall into one of ve clusters. - One group of adults with severe asthma has early onset allergic disease with a prominent T helper type cell (TH ) signature. This group has high levels of airway eosinophils, mast cells, IgE, and exhaled nitric oxide (FeNO). Candidate gene analyses in this cohort have indicated that TH in ammatory pathways are active in these patients. A second group of patients has adult onset asthma with notable eosinophilia generally in the absence of other important allergic disease. TH pathways are important in this group too, with notable patterns of interleukins (IL) such as IL- , IL- , and IL- in the blood. In a third group symptoms are mainly exercise induced. Mast cells play an important role in this group. A fourth group shows a minimal TH response but notable obesity. The h group shows a minimal TH response and notable sputum neutrophilia with a TH type cell response. Children may also fall into clusters, although the determinants of pediatric clusters do not mirror those of adult ones. Although e orts to identify phenotypic clusters help distinguish di erent subtypes of patients, clustering has not yet led to di erential treatment strategies. However, as newer treatments emerge, and as speci c biologic agents are developed, it is hoped that endotyping (de ning disease subtypes by predominant molecular mechanisms or treatment response) will lead to more targeted approaches. Pathogenesis The pathogenesis of asthma is complex and varies across clinical endotypes. Complex interactions between genetic, epigenetic, and environmental factors predispose patients to develop a limited number of dysfunctional immunologic regulatory patterns, which in turn dictate the presentation of clinical endotypes. Using classic genetic calculations from twin studies, it is estimated that asthma is roughly % heritable. Genomewide association studies have identi ed several candidate genes that are potentially involved in the pathogenesis of asthma. The ORMDL /GSDMD locus on chromosome q has been reproducibly associated with childhood onset asthma. Other genes, including IL on chromosome and IL RB on chromosome , have been variably implicated. Epigenetic changes in DNA methylation provide a means by which environmental changes can cause important changes in disease prevalence over time. Mouse models of allergen exposure have demonstrated epigenetic changes associated with genes involved in TH and TH responses. A study in humans identi ed increased methylation in a CpG island in the ACSL gene in response to high levels of maternal exposure to tra c related polycyclic aromatic hydrocar-
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expressed by and directed to these cells are important therapeutic targets.
Airway epithelial cells Airway epithelial cells are the main cells that form the barrier against mechanical stress, oxidant stress, allergens, pollutants, infectious agents, and leakage of endogenous solutes. These cells also have important roles in mucociliary clearance and signaling. Various types of pattern recognition receptors, including Toll-like receptor (TLR ), are expressed on epithelial cells, enabling responses to allergic and infectious stimuli. In asthma, epithelial cell derived cytokines and chemokines (including IL- , IL- , thymic stromal lymphopoietin (TSLP), and granulocytemacrophage colony stimulating factor (GM-CSF)) signal e ector cells (including basophils, eosinophils, mast cells, and lymphocytes) and dendritic cells to shape characteristic asthmatic immune response patterns to allergens, pollutants, and infectious agents.
Fig | Important host responses in the pathogenesis of asthma. Several asthma drugs in clinical trials target the cytokines (or their receptors) that are central to these pathways, including interleukin (IL- ), IL- , IL- , and IL- . TSLP=thymic stromal lymphopoietin bons. Interestingly, maternal smoking during pregnancy has been associated with epigenetic changes in children, although strong links to asthma have not been made. Several environmental exposures are associated with asthma. Severe infection with respiratory syncytial virus in infancy predisposes patients to asthma later in life, with an attributable rate of asthma due to the virus of roughly %, depending on age. Conversely, early exposure to environments with a high degree of microbial content (for example, rural farm environments and day care centres) is associated with lower odds of asthma compared with controls. The mechanism by which these e ects are mediated is unclear. However, a study in mice showed that administration of bacterial extracts to mice that were later subjected to allergic challenge inhibited allergic airway in ammation through IL- dependent pathways. As novel genomic targets are identi ed and new treatments are established, it is expected that asthma pharmacogenomics will result in a more personalized approach to the management of asthma. However, strategies directed by pharmacogenomics are probably several years away. Host responses in the pathogenesis of asthma Different asthma endotypes show variable degrees of inflammation, bronchial hyper-reactivity, mucus production, and remodeling. These pathologic changes are mediated by several airway cells and cells involved in the immune response ( g ). Important signaling molecules
Dendritic cells Like airway epithelial cells, dendritic cells are also directly exposed to the external environment. Pulmonary dendritic cells act as antigen presenting cells and express a variety of pattern recognition receptors on their cell surface. Dendritic cells can also be recruited to the airway in response to allergens and pathogens. They can be directly stimulated by surface binding of allergens or infectious agents or indirectly stimulated by airway epithelial cells (by mediators such as IL- , IL- , TSLP, and GM-CSF). Locally, dendritic cells can recruit eosinophils. Migration of dendritic cells through the lymphatics to regional lymph nodes is mediated by multiple factors including C-C chemokine receptor type (CCR ), CCR , and CCRL . Dendritic cells a ect T cell di erentiation and under certain circumstances generate the TH response commonly seen in atopic asthma. T cell subsets Several T cell subsets are important in asthma. Traditionally, TH cells have been thought to predominate, with characteristic raised levels of IL- , IL- , and IL- . ILand IL- promote in ammation (through signaling to eosinophils and B cells) and remodeling (through signaling to broblasts, airway smooth muscle, dendritic cells, and epithelial cells). IL- is crucial for B cell survival and maturation and for stimulating eosinophils. Some patients with asthma show a predominance of TH cells. This pattern can develop under the in uence of IL- and interferon (IFN- ) and is characterized by further production of IFN-. TH cells, which are CD positive T cells that express IL- , also play a role in a subset of patients with asthma. This pattern is unusual, in that the resulting TH pathways result in neutrophils being the primary e ector cells. TH cells are CD positive T cells that secrete IL- . Numbers of TH numbers are raised in people with atopy, and these cells promote allergic responses, probably through activation of mast cells. T regulatory cells, characterized by secretion of transforming growth factor (TGF-) and IL- , are thought to be important because of their role in blunting atopic responses.
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eosinophils is mediated by IL- , histamine, prostaglandin type , and eotaxins (through the CCR receptor). The survival of eosinophils is promoted by ILand apoptosis is signaled through binding of the siglecand siglec-F receptors. In addition to releasing toxic granular proteins, such as eosinophilic cationic protein and eosinophil derived neurotoxin, eosinophils secrete dozens of cytokines and chemokines, which promote in ammation through the TH pathway and airway epithelial damage.
Mast cells Mast cells are also important in the pathogenesis of asthma. Maintained near mucosal surfaces by IL- , these cells can be activated by binding of stem cell factor to the surface receptor c-kit, IgE crosslinking, or binding of tyrosine kinase. Activated mast cells are an important source of histamine, cysteinyl leukotrienes, and prostaglandins. These mediators are central to bronchoconstriction, vasodilation, and the allergic in ammatory cascade.
Fig | The airways in asthma undergo substantial structural remodeling. Histological section of a medium sized airway from a person without asthma and a patient with severe asthma stained with Movat's pentachrome stain. In asthma the epithelium (Ep) shows mucus hyperplasia and hypersecretion (blue), and thickening of the basement membrane (Bm). Smooth muscle (Sm) volume is also increased in asthma. Bv=blood vessel. Reproduced, under an open access agreement, from Wadsworth and colleagues. IL- , asthma, and glycosylation in airway epithelial repair. In: Chang C, ed. Carbohydrates--comprehensive studies on glycobiology and glycotechnology. InTech, B cells B cells are important in atopic asthma because they produce IgE. IL- and B cell activating factor promote B cell survival. Under the in uence of IL- or IL- , B cells need to bind to T cells (through CD and the CD ligand, respectively) to be activated to produce IgE, generally within regional lymph nodes. Secreted IgE is primarily bound through the high a nity Fc epsilon receptors on mast cells and basophils, and when crosslinked by aeroallergen causes these cells to degranulate and release their mediators. Innate lymphoid cells The innate lymphoid cell is a recently described e ector leukocyte that is stimulated by IL- and IL- (seen in response to viral illness) and requires the transcription factor ROR for signaling. These cells have the potential to di erentiate into macrophages and granulocytes while producing notable quantities of TH cytokines and stimulating eosinophils in the process. Eosinophils Eosinophils are bone marrow derived granulocytes that play a central role
in asthma. The biology of the eosinophil is complex, and the e ects of its secreted products are diverse. Cellular di erentiation in the bone marrow is mediated by IL , IL- , and GM-CSF. Recruitment of
Neutrophils Neutrophils probably play a role in speci c asthma endotypes. Recruited through TH pathways, neutrophil numbers are raised in patients with asthma, especially those who are relatively unresponsive to inhaled steroids. It has been di cult to prove that neutrophils are involved in the pathogenesis of severe asthma because the use of inhaled steroids may suppress eosinophilia and result in airway neutrophilia. - Airway remodeling Airway remodeling refers to a constellation of structural changes in asthma including epithelial injury, increased thickness of the basement membrane, increased volume of airway smooth muscle, goblet cell metaplasia, and increased airway angiogenesis and lymphangiogenesis ( g ). Airway epithelial injury Several biopsy studies have shown that injury, including disruption to tight junctions and cell denudation, occurs to the airway epithelium in asthma. - Epithelial cells demonstrate rapid repair mechanisms and initiate signal cascades central to asthma in response to several stimuli. This process is mediated at least in part by epithelial growth factor. Abnormal repair processes and decreased barrier function have also been demonstrated. Basement membrane thickness Biopsy studies have shown increases in reticular basement membrane thickness, thought to be mediated by myo broblasts, in patients with asthma. The functional relevance of this nding is unclear. In children these changes did not correlate with TH cytokine pro le or with future lung function. The role of connective tissue outside of the basement membrane is also unclear. It has also been reported that certain patients with asthma have notable hyperin ation and decreased elastic recoil, possibly because of changes in connective tissue.
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Airways smooth muscle mass Increased airways smooth muscle mass has been a recognized feature of asthma for decades. These increases are mediated in part by the release of cysteinyl leukotriene from eosinophils. Smooth muscle has a role in bronchoconstriction, which is triggered by several direct and indirect stimuli, and contributes to symptoms, exacerbations, and the remodeling process. The increase in smooth muscle mass is associated with increases in growth factors including TGF- and platelet derived growth factor. The muscle itself may also act as a secretory organ in asthma, promoting maladaptive growth and immunologic responses. A recent review of these properties highlighted IL- , IL- , TGF- , IL- , and tumor necrosis factor as important mediators in this process. Goblet cell metaplasia Goblet cell metaplasia is another important structural change that occurs in asthma. It has been observed in models of TH driven asthma, but is not a feature of TH models of asthma. The process seems to be dependent on the actions of the epidermal growth factor receptor as well as IL- and may be inhibited by IFN-. Calcium activated chloride channel proteins may mediate mucus hypersecretion at a downstream level. Currently available treatments As noted above, asthma is a disease that involves airway epithelial cells, cells involved in the immune response, and several structural cell types. Details of the interactions between these cell types and between currently available treatments and the host response are under investigation. Observations on the biologic response and e cacy of different drugs in speci c populations may lead to targeted therapies in the future. Although allergen avoidance and the management of comorbidities such as smoking and obesity are essential, drugs remain the cornerstone of treatment. Several drugs have been approved for asthma and the role of many of them has been well de ned in patients with mild to moderate disease, most recently in a comprehensive systematic review from the Global Initiative for Asthma. Short acting agonists counteract bronchoconstriction regardless of the trigger for contraction. In most patients with asthma, inhaled corticosteroids are a highly e ective controller therapy (de ned as a daily treatment designed to decrease the frequency of baseline symptoms and exacerbations that require short acting agonists). Consistent use of inhaled corticosteroids (such as beclometasone, budesonide, ciclesonide, uocinolide, uticasone, and mometasone) can improve asthma symptoms, quality of life, measures of airway function, hyper-responsiveness, and the frequency and severity of exacerbations. Long acting agonists (such as formoterol and salmeterol) are e ective when used in combination with inhaled corticosteroids in patients with symptoms or exacerbations. Leukotriene antagonists (such as montelukast) also show e cacy in asthma, alone or combined with other controller therapy, especially in patients with prominent allergic disease or exercise symptoms. Long acting muscarinic antagonists (such tiotropium and aclidinium) result in
bronchodilation and show modest e cacy as adjuncts to inhaled corticosteroids and long acting agonists. Omalizumab, a monoclonal antibody directed against IgE, is currently recommended by US National Heart, Lung, and Blood Institute's commissioned national asthma and education prevention program guidelines for use in severe treatment refractory asthma in patients with atopy on the basis of data from several randomized controlled trials (RCTs). It reproducibly decreases the number of exacerbations in adults and children with various severities of asthma. However, its use is limited by its high cost. Bronchial thermoplasty is an endoscopic procedure available at specialized centers that uses thermal energy to disrupt bronchial smooth muscle. Recent large open label studies have shown a sustained decrease in the frequency of exacerbations for as long as ve years in patients with severe asthma who undergo this procedure, suggesting that it has bene t in exacerbation prone populations.
Rationale for the development of new drugs to treat asthma
Currently available drugs have helped millions of patients
with respect to both the control of asthma symptoms and
asthma exacerbations. It has been estimated that - %
of patients will achieve symptom control with smoking ces-
sation; proper prescription of inhaled steroids and long
acting agonists; and optimization of drug availability
(through production of generic drugs), adherence, and
However, despite the general success of currently avail-
able asthma drugs, there are several reasons to pursue
new ones. As discussed above, the prevalence of asthma
is increasing and its burden on society remains high. To
date, there is no e ective preventive strategy for asthma or
a known cure. Unfortunately, the e ects of inhaled corti-
costeroids on asthma rapidly disappear when the drug is dis-
continued. Moreover, current asthma drugs generally do
not reverse or slow down most of the long term remodeling
changes that occur in various cell types in the airway. This
may be partly because inhaled corticosteroids to not inhibit
IL- , a mediator thought to play a role in remodeling.
Despite prescription of drugs to control asthma, many
patients still experience ongoing symptoms. Asthma
remains uncontrolled in about % of patients who are
adherent to their prescribed drugs. Patients with severe,
refractory asthma are responsible for a disproportionately
high use of medical resources.
Another rationale for the development of new drugs
is related to concerns about adherence, tolerability, and
the side e ects of conventional asthma drugs. Adherence
to inhaled regimens is problematic across many drug
Inhaled corticosteroids have e ects on
linear growth, bone density, adrenal function, cataracts,
The Salmeterol Multicenter Asthma
Research Trial raised concerns about the potential mor-
tality risk associated with long acting agonists (which
should always be used in conjunction with inhaled corti-
costeroids, preferably in one device). Montelukast was
associated with reports of behavioral instability in ,
but a review of clinical trials data did not demonstrate
a signi cant increase in the risk of behavioral related
adverse events or suicide.
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Furthermore, as we gain more information on asthma endotypes, novel drugs could provide the opportunity to personalize asthma management and directly target mechanisms responsible for the underlying disease.
Modifications of current treatments
Some of the new treatments aim to improve currently
successful ones--for example, by improving delivery
systems. Long acting muscarinic antagonists have
shown e cacy in RCTs in patients with uncontrolled
asthma on low dose inhaled corticosteroids (primary
outcome of morning peak ow) and those whose disease
remains uncontrolled receiving combined inhaled corti-
costeroids and long acting agonists (primary outcome
of time to rst exacerbation).
Ultra long acting agonists aim to maintain e cacy
while improving dosing convenience. Indacaterol, a
hour long acting agonist, has demonstrated safety
(in clinical trials settings) and e cacy in terms of air-
combination of inhaled corticosteroid and long acting
agonist--showed equivalent e cacy to uticasone
propionate-salmeterol in a phase III trial. A new class
of glucocorticoids, called dissociated corticosteroids, is
still in preclinical development despite promising data
published in animal models of asthma; these drugs are
aimed at maintaining e cacy while decreasing side
e ects. Research is also ongoing into compounds that
bypass or reverse the mechanistic causes of glucocorti-
coid resistance--such drugs would be useful in patients
who respond poorly to glucocorticoids.
Pathways amenable to future therapeutic intervention and emerging compounds Cytokine modulation As well as trying to improve existing drug classes, there is a strong push to develop biologic agents aimed at modulating cell signaling and the immunologic responses seen in asthma. The bene ts of omalizumab, especially with respect to exacerbations, have encouraged several lines of research into biologic agents that target pathways known to be central to the pathogenesis of asthma.
ILThe production of IL- is increased in asthma, both in the peripheral circulation and in the airways. It is produced by several cells including TH cells, natural killer cells, eosinophils, basophils, and CD positive cells. - The IL- receptor has a unique subunit as well as a subunit shared by the IL- and GM-CSF receptors, and it signals through multiple pathways including the JAK-STAT (Janus kinase-signal transducer and activator of transcription), Ras-MAPK (mitogen activated protein kinase), PI K-ERK (phosphatidylinositol- , -bisphosphate kinase-extracellular signal regulated kinase), and p -NF-B (nuclear factor light chain enhancer of activated B cells) pathways. ILenhances eosinophil growth, maturation, and migration, while inhibiting eosinophil apoptosis. - It also enhances basophil development.
Targeting the IL- pathway
Several clinical trials have involved manipulation of IL-
signaling in patients with asthma. Early trials of mepoli-
zumab, a monoclonal antibody that targets IL- , decreased
eosinophil counts in blood and sputum, but had no notice-
able e ects on airway function. However, in trials of
patients with sputum eosinophilia despite the use of high
dose inhaled corticosteroids or prednisone, mepolizumab
signi cantly decreased the number of exacerbations when
compared with placebo. -
Reslizumab, another monoclonal antibody to IL- ,
improved airway function in patients with persistent
sputum eosinophilia but had no signi cant e ect on
asthma symptoms or exacerbations when compared with
placebo. Results of phase IIb and III trials have not yet
been reported for benralizumab, a monoclonal antibody
that targets the IL- receptor , but this agent has been
shown to decrease eosinophils in blood, sputum, and air-
ways. A drug company sponsored phase III trial (Clinical-
Trials.gov identi er NCT
) of benralizumab is
currently in progress.
IL- and IL-
IL- and IL- are also central to the allergic response and
are found in increased levels in the airways and sputum of
people with asthma.
IL- is produced mainly by TH
cells and mast cells, whereas IL- is produced by a vari-
ety of cells including TH cells, mast cells, eosinophils, and basophils. - Although these two cytokines do not
show a high degree of sequence homology, they share a com-
mon receptor, IL- R. Both IL- and IL- a ect transcrip-
tion through the STAT signaling pathway. IL- promotes
TH cell development and B cell isotype switching, and it a ects the production of chemokines by the airway epi-
thelium. IL- promotes the allergic phenotype through
e ects on hematopoetic cells as well as airway epithelium,
smooth muscle, broblasts, and the endothelium.
Targeting the IL- and IL- pathways Several compounds in various phases of development aim to modulate IL- and IL- responses. Nebulized IL- R has been shown to be safe (in a clinical trial setting) and e cacious (in terms of symptoms and airway function) when compared in an RCT with placebo in the context of inhaled steroid withdrawal. In a placebo controlled RCT of AMG , an IL- R blocker, the intervention did not show statistical and clinical bene t in symptoms (as measured by the asthma control questionnaire) or lung function (as measured by pre-bronchodilator forced expiratory volume in one second). An RCT found that dupilumab, a monoclonal antibody that inhibits IL- R, was superior to placebo in preventing asthma exacerbations in the context of withdrawal of long acting agonists and inhaled corticosteroid in patients with blood or sputum eosinophilia despite the use of these two treatments. Lebrikizumab, a monoclonal antibody that targets IL- , was superior to placebo with respect to airway function in patients whose asthma was uncontrolled despite the use of inhaled corticosteroids. This e ect was most prominent in those with a high level of periostin, a stable blood marker of IL- activity.
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ILIL- , a cytokine produced by TH cells, plays an important role in the immunologic responses seen in asthma. Higher levels of IL- than normal have been found in the blood, sputum, and human airway cells of patients with asthma. - There are multiple ILreceptors, the functions of which may di er slightly. Receptor activation leads to the secretion of several inflammatory mediators including IL- , IL- , TNF, and GM-CSF, which ultimately leads to neutrophil recruitment. Targeting the IL- pathway Brodalumab is a human monoclonal antibody that binds the IL- R, e ectively inhibiting signaling of several members of the IL- family, including IL- . Three doses of brodalumab were compared with placebo in a phase IIa trial of adults with moderate to severe asthma. In this trial, safety was demonstrated, but e cacy (de ned by the primary outcome of change in the asthma control questionnaire) was not apparent in the group as a whole. A prespeci ed subgroup with high bronchodilator reversibility reported improved scores on the asthma control questionnaire (although the results were not adjusted for multiple comparisons). No other clinically meaningful di erences were found between the brodalumab groups and the placebo group. Of note, groups in this study were not strati ed by predetermined in ammatory pro les. Looking ahead to future asthma treatments Several novel classes of drugs are in the early phase of development. An antisense oligonucleotide CCR antagonist (co-administered with an antisense oligonucleotide targeting the c subunit of the IL- , IL- , and GMCSF receptors) has shown some early e cacy in phase II trials, decreasing sputum eosinophils in response to allergen challenge. CXC chemokine receptor antagonists, which may help in the management of neutrophilic disease by decreasing IL- activity, have shown some promise in early human trials by decreasing sputum neutrophilia in an ozone challenge model. The Toll-like receptor agonist QbG showed e cacy with respect to symptoms and airway function in the context of inhaled corticosteroid withdrawal. Tyrosine kinase inhibitors, which may a ect both airway in ammation and remodeling, are being tested in animal models and in early clinical trials. The safety evaluation of all of these novel treatments will require larger studies in patients who receive drugs for prolonged periods of time. Pediatric considerations Of the clinical trials referenced, only the DREAM study enrolled adolescents, with the other trials exclusively enrolling adults. Although limited information on safety in the pediatric population is available from trials of mepolizumab and reslizumab in conditions other than asthma, conclusions from the above trials on these agents should be extrapolated to younger age groups with caution.
Guidelines Because no biologic agents other than omalizumab are currently approved by regulatory authorities, there are no consensus guidelines from the large respiratory societies that advocate for use of biologic agents other than omalizumab at this time. Until these treatments are approved, it would be premature to recommend newer biologic agents in uncharacterized asthma populations. Owing to the heterogeneity of asthma, the selection of the most appropriate patients to demonstrate the clinical e cacy of newer agents in clinical trials remains a major challenge. This is also likely to be the case as some of these agents become available for clinical use. In the near future, the use of newer biologic agents will probably be limited to patients with severe asthma who have frequent exacerbations and a clearly de ned phenotype.
Future research The agents described above have shown potential bene t with respect to mechanistic endpoints. Safety remains a concern in patients who will probably need to use these immunomodulatory agents over prolonged periods because these agents could have an impact on the frequency of infections, autoimmune phenomena, and oncologic processes. Clinical e cacy has varied, and it is currently unclear whether these agents will have an e ect on symptoms, lung function, or the frequency or severity of exacerbations in larger populations (all of which are important). There are notable feasibility challenges to detecting all of these features over prolonged periods of time in appropriate populations. Moreover, certain populations--speci cally those with a lack of eosinophilia and decreased corticosteroid responsiveness--require extra attention.
Emerging strategies for improved asthma care: predictors
It is clinically challenging to predict which patients will
respond to a given treatment. It is also di cult to develop
clinical trials that can demonstrate e cacy of novel drugs
that are used in addition to existing treatments. This is
partly because the existing agents control symptoms and
exacerbations in a large proportion of patients. In addi-
tion, because asthma is a heterogeneous disorder made
up of various imperfectly de ned endotypes, there is a
risk of a type II error occurring in clinical trials of newer
drugs that evaluate patients without previous endotyp-
ing. As new asthma drugs emerge, it will be crucial to
identify biomarkers of responsiveness within patients to
guide clinical trial design and future clinical management
of patient subsets, especially with regard to the next gen-
eration of inhibitors of the TH in ammatory response. Several biomarkers are under investigation as pre-
dictors of responsiveness to treatment. FeNO, which is
associated with several markers of atopy, can be used
to predict responsiveness to omalizumab and inhaled
The evaluation of eosinophils in
blood and sputum can identify potential responders to
anti-IL- and anti-IL- therapies (with respect to exacer-
bations). Serum periostin seems to identify those patients
who will respond to lebrikizumab (with respect to airway
function). Measures of gene expression
in sputum can
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FUTURE research question
S What is the safety profile of biologic agents for the treatment of asthma that are used over long time periods? What is the long term efficacy of biologic agents for the treatment of asthma? Can these novel drugs prevent airway remodeling? What is the safety and efficacy profile of biologic asthma drugs in children? How will clinicians choose between different biologic therapies as they become available and can we identify novel biomarkers that can predict responsiveness? What are the potential therapeutic targets in patients with non-eosinophilic and corticosteroid resistant asthma? identify subtypes of asthma characterized as TH high and TH low, although currently this classi cation has not enabled the response to treatment to be predicted. Pharmacogenetics may also help identify potential responders, as was shown in phase III trials of the ILand IL- pathway antagonist pitrakinra and in several studies of receptor polymorphisms and response to agonists. - Ethnicity may be a predictor of responsive to treatment because the prevalence of asthma and response to drugs vary across races. Finally, metabolomics, the study of small molecules generated by cellular metabolic activity, may help distinguish asthma endotypes by processing large datasets rather than a single marker. Currently, FeNO and blood and sputum eosinophilia are the main predictive biomarkers in wide use and the others remain Research Tools
. Although FeNO is potentially available to primary care
physicians, it does not clearly affect management outcomes when added to other available tools. Management targeted towards normalization of sputum eosinophilia has been shown to decrease asthma exacerbations. However, di culties in acquiring sputum specimens and variability in interpretation preclude the use of these biomarkers in primary care. Conclusions Despite the notable clinical successes of inhaled corticosteroids, long acting agonists, and leukotriene modi ers, the burden of asthma, especially severe asthma, remains high. Several biologic pathways have been identi ed in the past years that may lead to e ective asthma treatments in the near future. Several novel classes of agent remain in preclinical or early phase development. Major hurdles in the advancement of asthma care include the design of clinical trials that can detect meaningful clinical changes in patients already receiving multiple e ective drugs and the identi cation of predictors of medication responsiveness. Contributors: Both authors substantially contributed to the design of the work and dra ing of the manuscript. JTO created the rst version of the manuscript. Both authors approved the nal version of this manuscript and agree to act as guarantors. Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: JTO has no nancial relationships with any organizations that might have an interest in the submitted work in the previous three years; MEW has received consulting honorariums from GlaxoSmithKline, Novartis, Merck, Boston Scienti c, NKT therapeutics, Teva, Regeneron, Boehringer Ingelheim, and Cytos. Provenance and peer review: Commissioned; externally peer reviewed.
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JT Olin, ME Wechsler